The human epidermal growth factor (EGF) family of receptor tyrosine kinases includes four members: EGFR (ErbB1, HER1), HER2 (c-Neu, ErbB2), HER3 (ErB3) and HER4 (ErbB4) (Hynes et. al. (1994)).
These HER receptors are predicted to consist of an extracellular ligand-binding domain, a membrane-spanning domain, a cytosolic protein tyrosine kinase (PTK) domain and a C-terminal phosphorylation domain (see, e.g., Kim et al., (1998)). Receptor activation via ligand binding leads to downstream signalling that influence cell proliferation, invasion and survival of normal cells and cancer cells.
Aberrant expression or activity of EGFR and HER2 have been correlated with many cancers including but not limited to lung, breast, ovarian, colon and bladder cancer and several targeted therapies have shown clinical efficiencies (see review of Hynes and Lane, Nature Rev., 2005).
There are two major classes of anti-HER therapeutics: ectodomain-binding antibodies (cetuximab, panitumumab and trastuzumab) and inhibitor of the tyrosine kinase domain (erlotinib, gefitinib, and lapatinib). A majority of these clinical therapies target EGFR and HER2 receptors.
However, despite their clinical success, these targeted therapies over EGFR and HER2 are limited due to acquired resistance problems. Indeed, patients that receiving these agents exhibit primary or intrinsic resistance to these inhibitors and for those who do not respond they eventually manifest secondary or acquired resistance (Kruser and Wheeler, Exp Cell Res, 2010). Moreover, these therapies are prescribed only at certain stages of malignant disease. Only 20-30% of patients with breast cancer over-expressing the HER2 receptor or demonstrating HER2 gene amplification in tumors, are eligible for treatment with Trastuzumab, reducing its therapeutic indications.
A further HER receptor, HER3 has also been described (Plowman (1990)), and it role in cancer has been explored (Horst et al. (2005); Xue et al. (2006)).
Binding of the ligand Heregulin (HRG) to HER3 receptor triggers the heterodimerization of HER3 with the others HER family receptors. Within the heterodimer, the HER3 kinase domain acts as an allosteric activator of its HER family partner (Campiglio M, et al. (1999); Karamouzis M V et al. (2007)).
The heterodimer HER2/HER3 has the strongest mitogenic activity in the HER family and is the major oncogenic signal leading to the proliferation and invasion of tumor cells in breast cancers (Citri et al. (2006); Lee-Hoeflich et al. (2008)).
Besides being over-expressed in numerous human cancers, such as breast, gastrointestinal, ovarian and pancreatic cancers, HER3 expression or signalling has been found associated with resistance to antibody-based therapies against the EGFR and HER2 (see for review Campbell et al., (2010)). In addition, it has been shown that tumors with low expression of HER2, which are not eligible for treatment with trastuzumab, often demonstrate a high expression of HER3 receptor, associated with poor prognosis (Travis et al. (1996); Naidu et al. (1998), Menendez et al. (2006)). In both cases, this HER3 programming promotes the formation of HER2/HER3 heterodimers.
The great potential of HER3 and the need to alternatives to therapy inhibiting EGFR or HER2 to face mechanisms of resistance, suggest that HER3-targeted agents, and in particular antibodies, might be used as efficient immuno-therapeutics.
Murine and chimeric anti-HER3 antibodies have been reported: U.S. Pat. No. 5,968,511, U.S. Pat. No. 5,480,968, WO03013602. Human anti-HER3 antibodies have also been reported: US2008/0124345, US2009/0291085A1.
Nevertheless the growing part of HER3 in many types of cancers and the complexity of cooperation and interdependence between the HER family and notably concerning the HER3 receptor, lead to the need of more drugs targeted this receptor as well as the complex HER2-HER3.